ASYMMETRIC SYNTHESIS OF L-NUCLEOSIDES AS ANTIHBV AGENTS

该项目是基于初步的研究结果， 一类核苷（+/-）-BCH-189及其类似物已显示出有效的 抗人B肝炎病毒的抗病毒活性。 我们已经合成 对映体纯的（-）-L和（+）-D-BCH-189 发现（-）-L-BCH-189是甘露糖的最适底物 抗人B肝炎病毒（HBV）的有效异构体。 而且 发现（-）-L-BCH-189的毒性显著低于（+）-D- BCH-189 （-）-L-BCH-189的上级抗HBV活性可能是 根据（+）-D-BCH-189易受 通过脱氧胞苷脱氨酶进行脱氨基，而（-）-L-BCH-189完全 在类似条件下对脱氨酶具有抗性。 因此， 应用程序建议扩展这一令人兴奋的初步发现 合成氧硫杂环戊烷L-的各种嘧啶和嘌呤类似物， 用于详尽的结构-活性关系研究的核苷 抗HBV。 此外，二氧戊环L-的不对称合成 将合成核苷及其C-核苷类似物。 合成的化合物的体外抗病毒活性将是 在来源于HepG 2细胞的2.2.15细胞中进行了评价， 用含有HBV的质粒转染。 此外，生物化学， 分子生物学和毒理学（体外）研究将 用（-）-L-BCH-189以及其他有前途的药物进行 候选人 此外，与国家研究所合作， 过敏症和传染病研究所，一种很有前途的候选药物 将在土拨鼠体内研究B型肝炎模型，以评估抗 HBV以及毒性。 该应用程序的长期目标是 发现和开发临床有效和安全的抗病毒药物 尽管存在巨大的问题， 世界

This project is based on the preliminary findings that an oxothiolane class of nucleosides (+/-)-BCH-189 and its analogues have shown potent antiviral activity against human hepatitis B virus. We have synthesized an enantiomerically pure (-)-L and (+)-D-BCH-189 from L-gulose and D- mannose, respectively, and discovered that (-)-L-BCH-189 is the most potent isomer against human hepatitis B virus (HBV). Furthermore, the (-)-L-BCH-189 was found to be significantly less toxic than the (+)-D- BCH-189. The superior anti-HBV activity of (-)-L-BCH-189 may be explained based on the fact that (+)-D-BCH-189 is susceptible to deamination by deoxycytidine deaminase while (-)-L-BCH-189 is completely resistant to the deaminase under the similar conditions. Thus, this application proposes the extension of this exciting preliminary findings to synthesize various pyrimidine and purine analogues of oxathiolane L- nucleosides for exhaustive structure-activity relationship studies against HBV. Additionally, assymmetric synthesis of dioxolane L- nucleosides as well as their C-nucleoside analogues will be synthesized. In vitro antiviral activity of the synthesized compounds will be evaluated in the 2.2.15 cells derived from HepG2 cells that were transfected with a plasmid containing HBV. Additionally, biochemical, molecular biological and toxicological (in vitro) studies will be performed with the (-)-L-BCH-189 as well as other promising drug candidates. Furthermore, in collaboration with the National Institute of Allergy and Infectious Diseases, a certain promising drug candidate will be studied in vivo woodchuck hepatitis B model to assess the anti- HBV as well as the toxicity. The long term goal of this application is to discover and develop clinically effective and safe antiviral agents for HBV which is currently lacking despite enormous problems in the world.